This proposal describes a 5-year training and research program that will allow the investigator to achieve her goal of becoming an independent patient-oriented researcher. She will use her expertise in international clinical research to improve reproductive health and survival of African women living with HIV-1. The proposed program will build on the candidate's extensive experience with international clinical research by improving her skills in study design and epidemiologic analysis of longitudinal data and improving her understanding of immunology and its application in patient-oriented research. The training plan incorporates an outstanding mentoring environment and involves collaboration between clinical researchers at the University of Washington and the University of Nairobi. Research Plan - HIV-1 infected pregnant women and contraception users have increased HIV-1 genital shedding and disease progression, but the mechanism behind these changes is poorly understood. Systemic T-cell immune activation has been linked to shedding and progression. We propose to measure systemic and local immune activation among these two groups of women. Aim 1) to determine whether postpartum hormonal contraception use affects systemic immune activation markers; Aim 2) to determine whether users of postpartum contraception have increased local immune activation, increased genital tract or breast milk HIV-1 shedding, and Aim 3) to describe differences in systemic immune activation in African HIV-1-seropositive and seronegative women throughout pregnancy and postpartum. The results of these analyses can be used to create a clearer picture of immunologic function in pregnancy and the postpartum period among HIV-1-infected women in Africa, to clarify mechanisms by which pregnancy and hormonal contraception may impact genital and breast milk HIV-1 shedding and disease progression, and ultimately to optimize recommendations for promoting appropriate family planning among these women. This opportunity will seed a larger research program to understand interactions of contraception, the immune system and HIV-1, and to use this knowledge to improve women's reproductive health. PUBLIC HEALTH RELEVANCE: Alison Roxby, MD, MSc is a Senior Fellow in the Division of Allergy and Infectious Diseases at the University of Washington. For this K23 award, the career development plan and proposed clinical research will allow the candidate mentored learning in immunology and epidemiology while investigating whether progesterone-based contraception and pregnancy are associated with increased local and systemic immune activation in Kenyan HIV-1-seropositive women. The research findings will elucidate progesterone's immunomodulatory properties and will form the basis of the candidate's independent career conducting patient-oriented research to improve the reproductive health of women with HIV.